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Pyrrole-type bet inhibitor and preparation method and application thereof

A technology of pyrrole and pyridine, which is applied to pyrrole BET inhibitors and their preparation. As a BET protein inhibitor, it can solve the problems of single structure, compound PK properties and in vitro properties, etc., and achieve easy-to-obtain raw materials and excellent drug preparation nature, good applicability

Active Publication Date: 2022-07-29
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above types of inhibitors are relatively simple in structure, and the PK properties and in vitro properties of the compounds are not very ideal

Method used

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  • Pyrrole-type bet inhibitor and preparation method and application thereof
  • Pyrrole-type bet inhibitor and preparation method and application thereof
  • Pyrrole-type bet inhibitor and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] 1-{2-Methyl-5-[5-(4-methylpiperazin-1-yl)-1H-imidazo[4,5-b]pyridin-2-yl]-4-phenyl-1H -pyrrol-3-yl}ethan-1-one (I-1)

[0085]

[0086] Step 1, 1-(2-Methyl-4-phenyl-1H-pyrrol-3-yl)ethan-1-one (I-1a)

[0087] At room temperature, 1.0 g (7.40 mmol) of 2-amino-1-phenylethan-1-one, 3.64 g (44.39 mmol) of sodium acetate and 0.87 g (8.73 mmol) of acetylacetone were dissolved in 10 mL of 50% ethanol aqueous solution. middle. After the addition was completed, the temperature was raised to 85 °C, N 2 The reaction was carried out under protection for 3h. After the reaction, the reaction solution was cooled to room temperature, 100 mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (100 mL×3), the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered with suction, evaporated to dryness, The crude product was purified by column chromatography to obtain 1.04 g of a pale yellow solid with a yi...

Embodiment 2

[0097] 1-{2-Methyl-5-[2-(4-methylpiperazin-1-yl)-7H-purin-8-yl]-4-phenyl-1H-pyrrol-3-yl}ethyl- 1-keto (I-2)

[0098]

[0099] Step 1, 2-(4-Methylpiperazin-1-yl)-5-nitropyrimidin-4-amine (I-2a)

[0100] Under ice bath conditions, 1 g (5.16 mmol) of 2,4-dichloro-5-nitropyrimidine was dissolved in 5 mL of dichloromethane, and the temperature was controlled to (-5) °C to 0 °C, and 0.88 g of 30% ammonia water was slowly added dropwise. (15.47 mmol). After dripping, the reaction was carried out at room temperature for 2h. After the reaction, 10 mL of water was added to the reaction solution, the aqueous phase was extracted with dichloromethane (1 mL×3), the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, suction filtered, evaporated to dryness, and the crude product was purified by column chromatography. 0.73 g of a pale yellow solid was obtained with a yield of 81.1%. ESI-MS m / z: 175.5[M+H] + .

[0101] At room temperature, 0.7 g (4.01...

Embodiment 3

[0107] 1-[5-(1H-imidazo[4,5-c]pyridin-2-yl)-2-methyl-4-phenyl-1H-pyrrol-3-yl]ethan-1-one (I- 3)

[0108]

[0109] Step 1, 1-[5-(1H-imidazo[4,5-c]pyridin-2-yl)-2-methyl-4-phenyl-1H-pyrrol-3-yl]ethan-1-one (I-3)

[0110] At room temperature, 0.2 g (1.83 mmol) of pyridine-3,4-diamine, 0.46 g (2.02 mmol) of I-1b and 0.031 g (0.183 mmol) of sodium metabisulfite were dissolved in 5 mL of absolute ethanol. After the addition, the temperature was raised to 80°C for 20h. After the reaction, the reaction solution was cooled to room temperature, 20 mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, suction filtered, evaporated to dryness, The crude product was purified by column chromatography to obtain 0.21 g of a pale yellow solid with a yield of 35.5%. ESI-MS m / z: 317.4[M+H] + . 1 H NMR (500MHz, Chloroform-d) δ 8.97 (d, J=2.0Hz...

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Abstract

The invention discloses pyrrole BET inhibitors and a preparation method and application thereof. The compound is the structure shown in general formula (I) or one or more of its tautomers, mesomers, racemates, enantiomers and diastereomers mixture, or a pharmaceutically acceptable salt thereof. Such compounds or their mixtures or their pharmaceutically acceptable salts use ethyl acetoacetate derivatives and aminoaryl ethyl ketones as starting materials, and obtain the compound of general formula (I) through continuous reaction, and the preparation method thereof is relatively simple and convenient. The preparation method is easy to obtain and has good applicability, and the medicament with the derivative as the active ingredient can be effectively used in the medicament for preventing and / or treating diseases related to BET protein.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to pyrrole-type BET inhibitors and a preparation method and application thereof, in particular to the use as a BET protein inhibitor. Background technique [0002] In recent years, tumors have become one of the leading causes of human death worldwide. Tumors generally have the characteristics of low overall cure rate and high recurrence rate. Therefore, prevention, treatment and inhibition of tumor recurrence have important scientific research value. It is urgent and challenging to realize tumor prevention and cure. [0003] Bromodomains (BRDs) are conserved protein domains that can specifically recognize acetylated lysine residues in histones. BRDs are present in different proteins and play key regulatory roles in chromatin assembly and gene transcription. Small molecule inhibitors of BRDs can interfere with the specific binding of BRDs domains to acetylated lysine, thereby blo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04C07D473/32C07D487/04C07D403/04A61K31/496A61K31/52A61K31/4985A61K31/5377A61K31/4184A61P19/02A61P19/06A61P35/00A61P35/02
CPCC07D471/04C07D473/32C07D487/04C07D403/04A61P19/02A61P19/06A61P35/00A61P35/02
Inventor 陈亚东陆涛孔博洪谦谦朱照宏唐伟方
Owner CHINA PHARM UNIV
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